Oyster-derived peptide DLAGRDLTDYLM attenuates dexamethasone-induced osteoporosis in rats: associations with lipid metabolism and bone remodeling signatures

Oyster-derived peptides have shown potential for bone protection; yet, the anti-osteoporotic activity of defined sequences remains insufficiently characterized in glucocorticoid-induced osteoporosis (GIOP). Here, DLAGRDLTDYLM (OP4), selected from oyster protein hydrolysates using a transgenic zebrafish model, was evaluated in a dexamethasone (DEX)-induced rat model. OP4 attenuated DEX-induced deterioration of femoral trabecular microarchitecture and improved serum markers associated with bone remodeling, evidenced by increased runt-related transcription factor 2 (RUNX2), osteocalcin (OCN), procollagen type I N-terminal propeptide (PINP), and osteoprotegerin (OPG), alongside reduced receptor activator of nuclear factor-κB ligand (RANKL) and cathepsin K (CTSK). Furthermore, OP4 treatment was associated with mitigated hepatic steatosis. Integrated serum and fecal metabolomics suggested that OP4 partially reversed DEX-associated disturbances in lipid metabolism, particularly involving unsaturated fatty acids and glycerophospholipids. In femoral tissue, transcriptomic and proteomic analyses, supported by targeted proteomics, indicated molecular changes associated with lipid metabolism, extracellular matrix organization, and the PI3K/Akt signaling. Collectively, these findings support that OP4 exerts protective effects on bone in DEX-treated rats, occurring concurrently with improvements in hepatic lipid accumulation, systemic lipid metabolic profiles, and molecular signatures associated with bone remodeling. Therefore, OP4 represents a potential food-derived peptide candidate for the adjunctive management of GIOP.